POS0329 CHONDROCYTE SUBPOPULATIONS AND CANONICAL PATHWAYS ASSOCIATED WITH HAND OSTEOARTHRITIS: DISCOVERY BY SINGLE-CELL TRANSCRIPTOMIC ANALYSIS AND VALIDATION BY TWO INDEPENDENT POPULATION-BASED STUDIES
Authors: H. LI, X. Jiang, Y. Xiao, Y. Zhang, W. Zhang, M. Doherty, N. Jacquelyn, C. LI, J. Ye, T. Sha, H. Lyu, J. Wei, C. Zeng, G. Lei
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Hand osteoarthritis is a common heterogeneous joint disorder with differences in aetiology and pathophysiology from the large weight-bearing knee or hip osteoarthritis.<sup>[1]-[3]</sup> Its pathophysiological mechanism remains largely unexplored, partially because of limited access to clinical sample tissues and lack of animal models.<sup>[2]</sup> To date, there is no known cure for hand osteoarthritis, indicating an urgent need for better understanding of the underlying mechanisms so that appropriate treatment strategies can be developed to target this disabling disease. <h3>Objectives</h3> We aimed to identify hand joint chondrocyte subpopulations and investigate the molecular mechanism of hand osteoarthritis by performing single-cell RNA sequencing (scRNA-seq) analysis, and verify the findings in two large independent population-based studies. <h3>Methods</h3> We obtained hand interphalangeal joints from five donors who had destructive forearm injury. Using scRNA-seq analysis, we analysed the cellular composition and subpopulation-specific gene expression of hand articular cartilage, and then compared these features between cartilages from joints with macroscopically confirmed osteoarthritis and those without osteoarthritis. To verify the findings, we conducted a Mendelian randomisation study in the UK Biobank and a cross-sectional study using data collected from the Xiangya Osteoarthritis Study. Figure 1 shows the schematic illustration of this study. <h3>Results</h3> Of 105,142 cells we identified 13 subpopulations, including a novel inflammatory chondrocyte subpopulation that specifically expressed genes related to inflammatory and immune response. Fibrocartilage chondrocytes represented a major source of osteoarthritis-related proteases and exhibited an extensive alteration of gene expression patterns in osteoarthritic cartilage compared with non-osteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend towards increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, in which the expression of iron overload-related genes, eg, <i>FTH1</i>, was elevated. These findings are further validated by two independent population-based studies. Among participants (n=332,668) in the UK Biobank, genetic predisposition to higher expression of <i>FTH1</i> mRNA significantly increased the risk of hand osteoarthritis (OR=1·07, 95%CI:1·02-1·11). Among participants (n=1,241) from the Xiangya Osteoarthritis Study, high levels of serum ferritin (encoded by <i>FTH1</i>), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis (<i>P</i>-for-trend=0·037). <h3>Conclusion</h3> Our datasets will be valuable as a rich resource for molecular and cellular exploration and open new possibilities for the research of molecular mechanism, drug development and precise treatment for hand osteoarthritis. Inflammatory and fibrocartilage chondrocytes are key subpopulations and ferroptosis may be a key pathway in hand osteoarthritis. Markers of these chondrocyte subpopulations, as well as ferroptosis inhibitors or iron chelators, could be focus of attention in future studies. <h3>References</h3> [1]Kloppenburg M, Kwok WY. Hand osteoarthritis--a heterogeneous disorder. <i>Nat Rev Rheumatol</i> 2011;8(1):22-31. [2]Marshall M, Watt FE, Vincent TL, et al. Hand osteoarthritis: clinical phenotypes, molecular mechanisms and disease management. <i>Nat Rev Rheumatol</i> 2018;14(11):641-56. [3]Haugen IK, Englund M, Aliabadi P, et al. Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study. <i>Annals of the rheumatic diseases</i> 2011;70(9):1581-6. <h3>Acknowledgements</h3> This work was supported by the National Natural Science Foundation of China (81930071, 82072502, 81902265), the National Natural Science Foundation Regional Innovation and Development Joint Fund (U21A20352), Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya Hospital, 2021LNJJ06, 2022LNJJ07), the Natural Science Foundation of Hunan Province (2022JJ20100), and Central South University Innovation-Driven Research Programme (2023CXQD031). <h3>Disclosure of Interests</h3> None Declared.